Fate of neutralizing and binding antibodies to IFN beta in MS patients treated with IFN beta for 6 years

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Abstract

An increasing number of evidence is showing that during prolonged treatment of relapsing–remitting multiple sclerosis (RRMS) with interferon (IFN) beta 1a or IFN beta 1b, the patients may develop serum anti-IFN antibody. It has been argued that some of the RRMS patients receiving IFN beta, who developed antibodies to IFN, lose them over time even though the treatment continues. To gain further insights into this issue, we performed a study to establish what happened to binding antibodies (BAB) and neutralizing antibodies (NAB) in 42 RRMS patients treated for 6 years with IFN beta 1a and/or IFN beta 1b.

While the data of BAB analysis did not allow to reach definite conclusions, the results on NAB development confirm that the presence of this type of antibodies is transitory; in fact, most of the positive patients reverted to seronegative, although the IFN treatment is still ongoing; the only patients who were positive for NAB at 6 years of treatment are those whose serum contains high concentration of them. The paper also shows that patients lose antibodies to IFN independently on the type of IFN used for the treatment.

In conclusion, the data indicate that the disappearance of the anti-IFN antibodies from the serum while the patients are still undergoing IFN treatment depends on the titer of antibodies but not on the type of IFN administered.

Introduction

It has been well established that antibodies to interferon (IFN) may develop during prolonged treatment with both types of IFN beta (IFN beta 1a and IFN beta 1b) currently available for the therapy of multiple sclerosis (MS) (for a review, see Ref. [1]). These antibodies are commonly divided in two types: binding antibodies (BAB) and neutralizing antibodies (NAB). BAB bind to different antigenic epitopes of the IFN beta molecule, some of them being not involved in activating interferon receptors; so far, no clear biological/clinical functions have been attributed to them. NAB are a subset of binding antibodies which react with the biological active sites of the IFN beta molecules, thus preventing the interaction of IFN with its receptor [2]; it has been reported that their development in patients may reduce or abrogate the biological and therapeutic effects of IFN beta [3], [4], [5], [6], [7], [8], [9].

Since the introduction of IFN beta in the therapy of MS, many papers have addressed the anti-IFN antibodies issue, and it has been shown the percentage of seroconversion in terms of both NAB and BAB may depend on the type of IFN beta administered, different human IFN beta preparations possibly possessing different immunogenicities [10], [11], [12] and that BAB are produced during IFN beta therapy at a significantly higher rate than NAB [13]. Despite structural and chemical differences between IFN beta 1a and IFN beta 1b [14], [15], [16] most probably responsible for the difference in their immunogenic activities, the two molecules are vastly identical and antigenically indistinguishable; thus, NAB developed in response to IFN beta 1a and IFN beta 1b are able to cross-react [17], [18].

It has also been proposed that formation of antibody to IFNs is only a temporary phenomenon. Indeed, in some instances, it has been demonstrated that the NAB's presence in the serum of IFN beta-treated patients is transitory, because these antibodies disappear from the serum even though the patient is still undergoing IFN treatment. Only few data, however, have been published so far on the fate of NAB and BAB in RRMS patients undergoing IFN beta therapy for more than 2 years [4], [7], [8].

To gain new insights into this unexpected and, at the moment, unexplained phenomenon, we performed a study to establish what happened to NAB and BAB in relapsing–remitting MS (RRMS) patients who continued to receive IFN beta 1a and/or IFN beta 1b over 6 years.

Section snippets

Patients and study design

This is a retrospective study. Specifically, it is an extension of a previous study (see [18], [19], [20] and the scheme in Fig. 1). Sixty-eight patients with clinically definite or laboratory-supported RRMS, age 15–45 years, disease duration of up to 10 years, expanded disability status scale (EDSS) score of 1–5 and at least two relapses in the previous 2 years, were randomly assigned to receive either 3 or 9 MIU (11 or 33 μg, respectively) of rIFN beta 1a (Rebif, Ares Serono, Geneva,

Results

Forty-two RRMS patients who had been treated for 6 years with IFN beta 1a only or with IFN beta 1a and IFN beta 1b were examined for the development of NAB or BAB.

The incidence of NAB and BAB seroconversion at 6 years in the examined patients is 7.1% (3:42) and 11.9% (5:42), respectively. We retrospectively examined all available sera from the patients who were specifically treated as summarized in Fig. 1 (see also Materials and methods). The results are shown in Fig. 2, which shows the

Discussion

Many cytokines are currently administered in man to achieve therapeutical benefits. For most of them, there are evidences that antibodies which can hinder their therapeutic efficacy can develop during prolonged therapy [1], [4], [7], [8], [9], [18], [24], [25]. Due to the large number of patients who are currently treated with IFNs, the anti-IFN antibody development has been studied with a special attention, and many aspects of this unusual and unexpected humoral response have been clarified.

Acknowledgements

This work was supported in part by a grant to G.A. from University “La Sapienza”—Rome (fondi MURST/Facolta' di Medicina e Chirurgia).

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